The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention.
One important host defense mechanism against pathogens is linking pathogen induced tissue damage to activation of inflammatory immune cascades. In such cases, connective tissue damage generates hyaluronan degradation fragments that efficiently bind to and activate the host's Toll-like receptor (TLR) immune pathway that is designed mainly to detect microbial invaders. This strategy should render stealth almost impossible for any pathogenic organism aiming to infiltrate deep tissues. However, successful pathogens can counter this strategy by tactically exploiting key features of their secreted hyaluronidase isoforms.
Among the bacterial hyaluronidases that have been characterized, two general hyaluronan fragmentation patterns have been described. Hyaluronidases from the streptococcal species S. pneumoniae and Group B Streptococcus (GBS), also known as Streptococcus agalactiae, produce disaccharides only. In contrast, evidence suggests that hyaluronidases expressed by Streptomyces and phylogenetically related P. acnes, produce larger fragments, similar in size to those generated by the immune-activating human hyaluronidase. Importantly, the disaccharides generated by streptococci do not activate immune defenses, whereas the larger hyaluronan fragments produced by Streptomyces and P. acnes appear to be highly immunogenic and pro-inflammatory. Considering all of these immunogenic, pro-inflammatory, and immune evasion effects, the inventors developed a number of therapeutic strategies described below.